Method of preventing asthmatic symptoms

ABSTRACT

5-Carboxypyrimidine derivatives and their pharmaceutically acceptable basic salts, and their use as antiallergy agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 299,871 filedOct. 24, 1972, and now U.S. Pat. No. 3,883,653.

BACKGROUND OF THE INVENTION

This invention relates to 5-carboxypyrimidines, and in particular to aseries of bis(4-hydroxy-5-carboxy-2-pyrimidinyl)phenoxy alkanes and2-substituted-4-hydroxy-5-carboxypyrimidines and their use as inhibitorsof allergic reactions, and in particular allergic asthma.

Allergic reactions, the symptoms resulting from an antigen-antibodyinteracton, manifest themselves in a wide variety of ways and diffuselydifferent organs and tissues. Among one of the most disabling anddebilitating of these allergic reactions is asthma, characterized byepisodes of breathlessness and wheezing.

Efforts to discover medicinal agents to alleviate the symptoms of thisabnormal physiologic state have been extensive. As early as 1910,Matthews, Brit. Med. J., 1, 441 (1910) reported the bronchodilatoreffects of epinephrine. Since then, Chen and Schmidt, J. Pharmacol.Exper. Therap., 24,339 (1924), reported the use of the alkaloidephedrine as an oral efficacious bronchodilator with the same spectrumof activity as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak.,197, 27 (1940), outlined the effects of the potent bronchodilatorisoproterenol and in 1968 Dugan, et al., J. Pharmacol. Exp. Ther., 164,290 (1968) reported the pharmacology of soterenol, a bronchodilator ofgreater potency, duration and oral effectiveness.

Although the aforementioned bronchodilators represent outstandingcontributions toward the treatment of asthma, they all share the sameundesired side effect of cardiac stimulation.

Recently, Cox and co-workers, Adv. in Drug Res., 5, 115 (1970),described the pharmacology of disodium cromoglycate, an agent useful inthe treatment of bronchial asthma. Although this compound is unrelatedto the sympathomimetic amine bronchodilators previously mentioned, andmediates its bronchodilator effects by a unique mechanism of action, itsuffers from the lack of oral efficacy.

Netherlands patent application 7008625 describes the preparation of awide variety of pyrimidines and pyrazines including2-aryl-4-hydroxy-5-carboxypyrimidines, claiming utility as antipyretic,analgesic, diuretic, hypoglycemic, antifibrinolytic and antiinflammatoryagents.

Mitter, et al., Quart. J. Indian Chem. Soc., 2, 61 (1925), has reportedthe synthesis of 2-phenyl-, 2-tolyl- and2-anisyl-4-hydroxy-5-carboxypyrimidines, while the 2-phenyl congener isreported by McCarthy, et al., J. Med. Chem., 7, 68 (1964). No utilitywas disclosed for these analogs.

SUMMARY OF THE INVENTION

The antiallergy agents of the present invention are represented by theformulae: ##SPC1##

And the pharmaceutically acceptable basic salts thereof, wherein R₁ ishydrogen, bromo, chloro, fluoro or methoxy; n is an integer of 1 to 3;Ar is pyridyl, thienyl, furyl, phenyl or phenyl substituted by hydroxy,methyl, methoxy, nitro, chloro, fluoro, 3,3-dimethoxy, 3,4,5-trimethoxyor alkanoylamino containing from 2 to 3 carbon atoms; and m is aninteger of 0 or 1.

The preferred compounds of formula I are those wherein R₁ is hydrogenand n is an integer of 1 or 2, while the preferred compounds of formulaII are those where Ar is pyridyl, phenyl or substituted phenyl whereinthe substituent is methoxy or chloro and m is 0, and where m is 1 and Aris methoxyphenyl.

In addition to their usefulness as agents in the treatment of allergicasthma, many of the compounds of the present invention manifest thisactivity following oral administration.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the process employed for the preparation of the 5carboxypyrimidine derivatives of the present inventon of formula I, thefollowing scheme is illustrative: ##SPC2##

In practice, the amidine hydrochloride, wherein n and R₁ are aspreviously indicated, is contacted with diethyl ethoxymethylenemalonate,a commercial reagent, in a suitable inert solvent.

Such a reaction-inert solvent comprising the liquid phase of saidreaction should be one which does not react to any appreciable extentwith either the reactants or products of said reaction. The preferredsolvents include (lower)alkanols, acetonitrile, tetrahydrofuran andN,N-di(lower)alkyl-(lower)alkylamides. The especially preferred solventis ethanol.

At least two moles of the malonate per mole of the amidine should beemployed, and at least two moles of a suitable base, usually sodiummethoxide or ethoxide, plus as much as a 10-20% excess are used.

The described reaction is best carried out at elevated temperatures,preferably the reflux temperature of the reaction solvent. Under theseconditions, the reaction time may vary from 12 to 36 hours.

The intermediate ester is conveniently isolated by filtration of thecooler reaction mixture followed by suspension of the solid in anaqueous medium to which sufficient acid has been added to provide a pH1-2.

The intermediate product resulting from the above described reaction isconverted to the final product or a basic salt thereof by hydrolysis ofthe ester moiety under basic conditions.

Experimentally, said ester is heated with an excess of an alkali metalhydroxide, e.g., potassium hydroxide, in ethanol or methanol to whichhas been added a moderate amount of water. The reaction generallyrequires several hours at the reflux temperature at which timeadditional alcohol is added to aid in the precipitation of the potassiumsalt. The salt may be utilized as the antiallergy agent or, alternately,can be converted to the free acid or a different salt.

The starting materials leading to the synthesis of the compounds offormula I are either commercial reagents or are readily prepared bymethods familiar to one skilled in the art. For example, the requisiteamidines are synthesized by the method of Berg, et al., J. Chem. Soc.,642 (1949), while the 4-hydroxybenzonitriles employed for theirsynthesis are readily available through procedures described in theliterature.

Compounds of formula II are prepared in a similar manner to those offormula I and comprises condensation of an aryl- or arylmethylamidinewith diethyl ethoxymethylenemalonate and is previously described by Toddet al., J. Chem. Soc., 364 (1937).

The appropriate amidine starting materials leading to the preparation ofcompounds II are synthesized by methods well known in the art, forexample, those outlined by Wagner and Zook, "Synthetic OrganicChemistry," John Wiley & Sons, Inc., New York, 1953, page 634.

Hydrolysis of the intermediate ester to the corresponding acid or saltsthereof is effected in a manner similar to that for the compounds offormula I. The salts, however, are generally more soluble and it istherefore preferred that the hydrolysis mixture be cooled and acidifiedwithout isolation of the basic salt.

As has been previously noted, a characteristic feature of the acidiccompounds I and II of the instant invention is their ability to formbasic salts. Acid congeners of the present invention are converted tobasic salts by the interaction of said acid with an appropriate base inan aqueous or non-aqueous medium. Such basic reagents suitably employedin the preparation of said salts can vary in nature, and are meant tocontemplate such bases as organic amines, ammonia, alkali metalhydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well asalkali earth metal hydroxides, hydrides, alkoxides and carbonates.Representative of such bases are ammonia, primary amines such asn-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine,p-toluidine, ethylamine, octylamine, tertiary amines such asdiethylaniline, N-methylpyrrolidine, N-methylmorpholine and1,5-diazabicyclo-[4,3,0]-5-nonene; sodium hydroxide, potassiumhydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide,magnesium hydroxide, calcium hydride and barium hydroxide.

In a similar manner, treatment of the basic salts with an aqueous acidsolution, e.g., mono-, di- or tribasic acid results in the regenerationof the free acid form. Such conversions are best carried out as rapidlyas possible and under temperature conditions and method dictated by thestability of said acid products. The acids thus generated can bereconverted to the same or a different basic salt.

In the utilization of the chemotherapeutic activity of those compoundsof the present invention which form basic salts, it is preferred, ofcourse, to use pharmaceutically acceptable salts. Althoughwater-insolubility, high toxicity, or lack of crystalline nature maymake some salt species unsuitable or less desirable for use as such in agiven pharmaceutical application, the water insoluble or toxic salts canbe converted to the corresponding acids by decomposition of the salts asdescribed above, or alternately they can be converted to any desiredpharmaceutically acceptable basic salt. The said pharmaceuticallyacceptable salts preferred are those wherein the cation is ammonium,sodium or potassium.

As previously noted, 5-carboxypyrimidines of the present invention areall readily adapted to therapeutic use in preventing allergic symptomsin mammalian subjects by administering to said subject an effectiveamount of a compound of formulae I or II. Especially of interest is thealleviation of the symptoms of allergic asthma. Compounds notable forthis therapeutic use include bis(4-[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]phenoxy)methane, 1,2-bis(4-[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]phenoxy)ethane,2-phenyl-4-hydroxy-5 -carboxypyrimidine, 2-(p-methoxyphenyl)-4-hydroxy-5-carboxypyrimidine,2-(p-chlorophenyl)-4-hydroxy-5-carboxypyrimidine, 2-(3'-pyridyl)-4-hydroxy-5 -carboxypyrimidine,2-(4'-pyridyl)-4-hydroxy-5-carboxypyrimidine and2-(p-methoxybenzyl)-4-hydroxy-5-carboxypyrimidine.

The 5-carboxypyrimidines and the pharmaceutically acceptable basic saltsthereof, which are useful antiallergy agents in mammals may beadministered either as individual therapeutic agents or as mixtures oftherapeutic agents. They may be administered alone, but are generallyadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice. Forexample, they may be combined with various pharmaceutically acceptableinert carriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, aerosol sprays, aqueous suspensions or solutions,injectable solutions, elixirs, syrups and the like. Such carriersinclude solid diluents, or filters, sterile aqueous media and variousnontoxic organic solvents. Moreover, the oral pharmaceuticalcompositions of this invention may be suitably sweetened and flavored bymeans of various agents of the type commonly used for this purpose.

The particular carrier selected and the proportion of active ingredientto carrier are influenced by the solubility and chemical nature of thetherapeutic compounds, the chosen route of administration and the needsof the standard pharmaceutical practice. For example, where thosecompounds are administered orally, those compounds of formula II, intablet form, excipients such as lactose, sodium citrate, calciumcarbonate and dicalcium phosphate may be used. Various disintegrantssuch as starch, alginic acids, and certain comples silicates, togetherwith lubricating agents such as magnesium stearate, sodium laurylsulphate and talc, may also be used in producing tablets for the oraladministration of these compounds. For oral administration in capsuleform, lactose and high molecular weight polyethylene glycols are amongthe preferred materials for use as pharmaceutically acceptable carriers.Where aqueous suspensions are to be used for oral administration, thecompounds of this invention may be combined with emulsifying orsuspending agents. Diluents such as ethanol, propylene glycol, glycerineand their combinations may be employed as well as other materials.

For the purpose of parenteral administration and inhalation, solutionsor suspensions of the instant compounds of formulae I and II in sesameor peanut oil or in aqueous propylene glycol solutions can be employed,as well as sterile aqueous solutions of the solution acid addition saltsdescribed hereinafter. These particular solutions are especially suitedfor intramuscular and subcutaneous injection purposes. The aqueoussolutions, including those of the acid addition salts dissolved in puredistilled water, are also useful for intravenous injection purposesprovided that their pH is properly adjusted beforehand. Such solutionsshould also be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose.

The compounds may be administered to asthmatic subjects suffering frombronchoconstriction by means of inhalators or other devices which permitthe active compounds to come into direct contact with the constrictedareas of the tissues of the subject. When administeed by means of aspray formulated as a 1% solution in an aqueous or nonaqueous solvent,e.g., freons, utilization several times a day is preferred.

It is necessary that the active ingredient form a proportion of thecomposition such that a suitable dosage form will be obtained.Obviously, several dosage unit forms may be administered at about thesame time. Although compositions with less than 0.005% by weight ofactive ingredient might be used in certain instances, it is preferred touse compositions containing not less than 0.005% of the activeingredient; otherwise the amount of carrier becomes excessively large.Activity increases with the concentration of the active ingredient. Thecomposition may contain 10, 50, 75, 95 or an even higher percentage byweight of the active ingredient.

Regarding the test procedure employed to evaluate the compounds of thepresent invention, it has been found that the Passive CutaneousAnaphylaxis (PCA) reaction demonstrates an excellent correlation betweenactivity for compounds in this test and their utility in the treatmentof alleric asthma. The ability of agents to interfere with PCA reactionsis measured in male Charles River Wistar rats, 170-210 g. Reaginicantisera is prepared according to Mota, Immunology, 7, 681 (1964), usinghen egg albumin and B. pertussis. Hyperimmune antisera to hen eggalbumin is prepared according to Orange, et al, J. Exptl. Med., 127, 767(1968). Forty-eight hours prior to antigen challenge the reaginicantisera is injected intradermally into the shaved skin of a normalrat's back; 5 hours before challenge the hyperimmune antisera issimilarly injected; 5 hours later, at a third site, 60 mcg histaminedihydrochloride is injected i.d. as a check for antihistaminic andunspecified types of blockade; the compounds of the instant invention orsaline are then administered i.v. or orally immediately followed by 2.5mg. Evan's blue dye and 5 mg. egg albumin in saline. Thirty minuteslater the animals were asphyxiated using chloroform and the skin of theback removed and reversed for observation. A score is assigned eachinjection site equal to the product of the diameter of the site in mm.and a grade of 0.1, 0.5, 1, 2, 3 or 4 proportional to intensity of dyecoloration. The scores for a given injection site are summed for eachgroup of 8 animals and compared to the saline treated controls. Thedifference is expressed as percent blockade due to the compoundemployed.

Compounds representative of those in the present invention are tested bythe aforementioned procedure, and the resulting activities are reportedas the % protected animals. Disodium Cromoglycate, a commercialantiallergy agent, is included for comparison.

    __________________________________________________________________________    % Protected in PCA Screen                                                             DOSE                                                                          1 mg./kg.                                                                             10 mg./kg.                                                                             30 mg./kg.                                                                             100 mg./kg.                                 R.sub.1                                                                          n    I.V.    I.V.     ORAL     ORAL                                        __________________________________________________________________________    H  1    --      29       0        0                                           H  2    50      98       0        0                                           __________________________________________________________________________

    __________________________________________________________________________                  Dose                                                                          1 mg./kg.                                                                           10 mg./kg.                                                                           30 mg./kg.                                                                           100 mg./kg.                                 Ar          m I.V.  I.V.   ORAL   ORAL                                        __________________________________________________________________________    C.sub.6 H.sub.5 --                                                                        0 42    96     --      0                                          p-CH.sub.3 C.sub.6 H.sub.4 --                                                             0 50    --     --     --                                          m-CH.sub.3 C.sub.6 H.sub.4 --                                                             0 25    --     --     --                                          p-ClC.sub.6 H.sub.4 --                                                                    0 --    57     --     --                                          m-NO.sub.2 C.sub.6 H.sub.4 --                                                             0 43    86     --     20                                          p-CH.sub.3 OC.sub.6 H.sub.4 --                                                            0 57    100    20     91                                          p-HOC.sub.6 H.sub.4 --                                                                    0 50    --     --     --                                          3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 --                                                 0 33    --     --     --                                          3,4,5-(CH.sub.3 O).sub.3 C.sub.6 H.sub.2 --                                               0 50    --     --     --                                          p-CH.sub.3 OC.sub.6 H.sub.4 --                                                            1 --    60     --     --                                          3,4-(CH.sub.3 O).sub.2 H.sub.3 --                                                         1 17    --     --     --                                          2-pyridyl   0 --    30     --     --                                          3-pyridyl   0 50    100    --     27                                          4-pyridyl   0 14    86     --     36                                          Disodium chromoglycate                                                                    63                                                                              --     0      0                                                 __________________________________________________________________________

Regarding utility, and in particular the dosage regimen, obviously thephysican will ultimately determine the dosage which will be mostsuitable for a particular individual, and it will vary with age, weightand response of the particular patient as well as with the nature andextent of the symptoms and the pharmacodynamic characteristics of theparticular agent to be administered. Generally, small doses will beadministered initially, with a gradual increase in the dosage until theoptimum level is determined. It will often be found that when thecomposition is administered orally, larger quantities of the activeingredient will be required to produce the same level as produced byasmall quantity administered parenterally.

Having full regard for the foregoing factors, it is considered that aneffective daily dosage of the compounds of the present invention inhumans of approximately 20 to 200 mg. per day, with a preferred range ofabout 75 to 180 mg. per day in single or divided doses, or at about 1 to3 mg./kg. of body weight will effectively alleviate bronchoconstrictionin human subjects. These values are illustrative, and there may, ofcourse, be individual cases where higher or lower dose ranges aremerited.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE 1 Bis(4-[4'hydroxy5'-carboxy-2'-pyrimidinyl]phenoxy)methane I;R₁ = H and n = 1)

A. Bis(4-cyanophenoxy)methane

To a suspension of 48 g. (0.4 mole) of 4hydroxybenzonitrile in 200 ml.of ethanol is added portion-wise 200 ml. of ethanol containing 9.2 g. ofreacted sodium metal, followed by the dropwise addition of 53.4 g. (0.2mole) of methylene iodide. The reaction mixture is heated to refluxovernight, cooled and filtered. The first crop of crude product consistsof 2.0 g., m.p. 130°-138°C., while the second crop, obtained byconcentration of the filtrate to one-third volume, is 10.2 g., m.p.137°-142°C. The crops are combined and recrystallized from acetic acid,9.8 g., m.p. 145° C.

B. Bis(4-guanylphenoxy)methane dihydrochloride

Into a slurry of 9.8 g. (0.039 mole) of bis(4-cyanophenoxy)methane in 20ml. of chloroform containing 7 ml. of ethanol is bubbled hydrogenchloride gas until 3.3 g. has been absorbed, and the resultinghomogenous solution allowed to stand at room temperature for two days.The resulting suspension is stirred while 170 ml. of an 8 % ammonia inethanol solution is added. After stirring for several hours, the mixtureis again allowed to stand for two days. The insolubles are filtered,ether added to the filtrate, and the precipitated product is collectedby filtration and dried, 8.4 g., m.p. 225° C. dec.

C. Bis(4-[4'-hydroxy-5'-carbethoxy-2'-pyrimidinyl]phenoxy]methane

A suspension of 8.0 g. (22 m moles) of bis(4-guanylphenoxy)methanedihydrochloride in 250 ml. of ethanol, under a nitrogen atmosphere istreated with 9.5 g. (44 m moles) of diethyl ethoxymethylenemalonatefollowed by 2.6 g. (48 m moles) of sodium methoxide. After refluxing for18 hrs. the mixture is filtered and the filtrate diluted with 250 ml. ofwater. The pH of the aqueous mixture is adjusted to ˜1.0 by the additionof 12N hydrochloric acid and the precipitate is filtered and dried, 6.4g., m.p. 280° C. dec.

D. Bis(4-[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]phenoxy)methane anddipotassium Salt

Two and seven-tenths grams (5 m moles) of the above ester is added to100 m. of ethanol containing 50 ml. of water and 1.7 g. of potassiumhydroxide, and the solution heated to reflux for 18 hrs. Additionalethanol is added to precipitate the dipotassium salt as thetetrahydrate, 1.6 g.

Anal. Calc'd for C₂₃ H₁₄ O₈ N₄ K₂.4H₂ 0: C, 39.4; H, 2.9; N, 8.0. Found:C, 39.5; H, 2.7; N, 7.9.

The free acid is obtained by treating an aqueous solution of thedipotassium salt with sufficient 6N hydrochloric acid to provide a pH of1-2 followed by filtration and drying of the precipitated product.

EXAMPLE 2 1,2-Bis(4'[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]phenoxy)ethaneI; R₁ = H and n = 2)

A. 1,2-Bis(4-cyanophenoxy)ethane

A solution of 200 ml. of ethanol containing 9.2 g. (0.4 mole) of reactedsodium metal is added to a suspension of 48 g (0.4 mole) of4-hydroxybenzonitrile, followed by 37.2 g. (0.2 mole) of1,2-dibromoethane, and the resulting mixture heated to reflux for 18hrs. An additional 18.9 g. (0.1 mole) of the dibromide is added andheating continued for 18 hrs. Finally, 9.5 g. (0.5 mole) more of thedibromide is added and heating continued for 4 hrs. The reaction mixtureis cooled and the precipitate, which consists of potassium bromide andthe desired intermediate, is subsequently slurried in water andfiltered, 30 g., m.p. 196°-197° C.

1,2-Bis(4-guanylphenoxy)ethane dihydrochloride

Hydrogen chloride gas is bubbled into a suspension of 26.0 g. (0.1 mole)of 1,2-bis(4-cyanophenoxy)ethane in 25 ml. of chloroform containing 12ml. of ethanol until 7.3 g. has been absorbed. After the suspension hasremained at room temperature for two days, it is treated with 90 ml. ofan 8% ammonia in ethanol solution, and allowed to stir for an additionaltwo days. The solids are filtered and extracted with 500 ml. of hotwater, and the aqueous solution concentrated to 100 ml. The precipitatewhich crystallizes from the cooled, concentrated aqueous extract isfiltered and dried, 6.0 g., m.p. 320° C. dec.

C. 1,2-Bis(4'-[4'-hydroxy-5'-carbethoxy-2'-pyrimidinyl]phenoxy)ethane

To a suspension of 5.6 g. (15 m moles) of the above guanyl compound in60 ml. of ethanol and maintained under a nitrogen atmosphere is added6.5 g. 30 m moles) of diethyl ethoxymethylenemalonate and 1.6 g. (30 mmoles) of sodium methoxide, and the suspension stirred at roomtemperature overnight and then at 45°C. for 18 hrs. An additional 1.6 g.of sodium methoxide is added and heating at 75°C. continued for 18 hrs.

The solids are filtered, suspended in water and the aqueous phase isseparated and acidified with 12N hydrochloric acid to pH 1.0. Theresulting precipitate is filtered and dried, 5.6 g., m.p. 310° C. dec.

D. 1,2-Bis(4-[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]phenoxy)ethane anddipotassium salt

A solution of 4.0 g. (7.4 m moles) of the above ester in 150 ml. ofethanol containing 80 ml. of water and 2.7 g. of potassium hydroxide isheated to reflux under an atmosphere of nitrogen. After 16 hrs. thesolution is cooled in an ice bath, diluted with additional ethanol, andthe crystallized salt filtered and dried, 2.3 g., m.p. >300°C.

The free acid is obtained by acidification of an aqueous solution of theabove salt with 6N hydrochloric acid.

EXAMPLE 3 1,3-Bis(4-[4'-hydroxy-5'-carboxy-2'-primidinyl]phenoxy)propaneI; R₁ = H and n = 3)

A. 1,3-Bis(4-cyanophenoxy)propane

In a manner similar to the procedures of Examples 1A and 2A, 48.0 g.(0.4 mole) of 4-hydroxybenzonitrile, 9.2 g. (0.4 mole) of sodium metaland 40.0 g. (0.2 mole) of 1,3-dibromopropane provided 41.5 g. of thedesired intermediate, m.p. 186-187° C.

B. 1,3-Bis(4-guanylphenoxy)propane dihydrochloride

Hydrogen chloride gas is bubbled into a suspension of 41.0 g. (0.147mole) of the above cyano compound in 100 ml. of chloroform and 20 g. ofethanol until the theoretical amount has been added, 10.8 g. Afterremaining at room temperature for 3 days, additional hydrogen chlorideis added over a period of 30 min. and the mixture allowed to remain atroom temperature for one week.

The solids are filtered, and ether added to the filtrate. Theprecipitate which slowly crystallizes is filtered and dried, 4.5 g.

C. 1,3-Bis(4-[4'-hydroxy-5'-carbethoxy-2'-pyrimidimyl]phenoxy)propane

In a manner similar to the procedures of Examples 1C and 2C, the desiredintermediate is obtained by the reaction of 3.85 g. (0.01 mole) of1,3-bis(4-guanylphenoxy)propane, 4.32 g. (0.02 mole) of diethylethoxymethylenemalonate and 1.1 g. (0.02 mole) of sodium methoxide in 50ml. of ethanol.

D. 1,3-Bis(4-[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]phenoxy)propane anddipotassium salt

A mixture of 2.8 g. (5 m moles) of1,3-bis(4-[4'-hydroxy-5'-carbethoxy-2'-pyrimidinyl]phenoxy)propane and1.7 g. of potassium hydroxide in 100 ml. of ethanol containing 50 ml. ofwater is heated to reflux overnight. The solution is cooled, dilutedwith 100 ml. of ethanol and the crystallized potassium salt filtered anddried.

The free acid is obtained by adjusting the pH of an aqueous solution ofthe above salt to 1, followed by filtration and drying of theprecipitated solids.

EXAMPLE 4

Following the procedures of Examples 1, 2 or 3, and employing therequisite starting chemical reagents, the bis(phenoxy)alkanes listedbelow are synthesized.

    __________________________________________________________________________                  n      R.sub.1  n       R.sub.1                                 __________________________________________________________________________                  1      2-F      1       2-CH.sub.3 O                                          3      2-F      2       2-CH.sub.3 O                                          1      2-Cl     3       2-CH.sub.3 O                                          2      2-Cl     2       3-CH.sub.3 O                                          3      2-Cl     2       2-CH.sub.3                                            2      3-Cl     3       2-CH.sub.3                                            1      2-Br     1       3-CH.sub.3                                            3      2-Br     2       3-CH.sub.3                                            3      3-Br     3       3-CH.sub.3                              __________________________________________________________________________

EXAMPLE 5 2-Phenyl-4-hydroxy-5-carboxypyrimidine (II; Ar = C₆ H₅ and m =0)

To a solution of ethanol containing 1.32 g. (0.058 mole) of reactedsodium metal is added 12.4 g. (0.058 mole) of diethylethoxymethylenemalonate followed by 10.0 g. (0.058 mole) of benzamidinehydrochloride hydrate, and the mixture heated to reflux overnight. Thereaction mixture is cooled and filtered and the filtrate concentrated toan oil which on addition to 200 ml. of water and acidificationprecipitates a white solid. The intermediate ester is filtered anddried, 9.0 g., m.p. 209-210° C. A small sample is recrystallized frommethanol, m.p. 210°-211° C.

Three grams (12 m moles) of the above ester is heated in 75 ml. ofethanol containing 1.34 g. of potassium hydroxide to the refluxtemperature for 5 hrs. The mixture is cooled, filtered and the filtratediluted with 50 ml. of water and acidified to pH 1 to 6N hydrochloricacid. The crystallized product is filtered and dried, 2.0 g., m.p. 274°C. dec.

Anal. Calc'd for C₁₁ H₈ O₃ N₂ : C, 61.1; H, 3.7; N, 13.0. Found: C,60.7; H, 3.9; N, 13.0.

EXAMPLE 6 2-(m-Tolyl)-4-hydroxy-5-carboxypyrimidine (II; Ar = m-CH₃ C₆H₄ and m = 0)

To a suspension of 17.0 g. (0.1 mole) of m-toluamidine hydrochloride in200 ml. of ethanol and under a nitrogen atmosphere is added successively21.6 g. (0.11 mole) of diethyl ethoxymethylenemalonate and 5.9 g. (0.11mole) of sodium methoxide. After heating the reaction mixture to refluxfor several hours, it is cooled and filtered. The filtered solids aredissolved in water and treated with sufficient 12N hydrochloric acid toprovide a pH 1. The precipitated solids are filtered and dried, 10.2 g.,m.p. 160°-161° C.

A solution of 5.16 g. of the above ester intermediate in 200 ml. ofethanol containing 2.24 g. of potassium hydroxide is heated to refluxfor 2.5 hrs. The solution is cooled and acidified with 12N hydochloricacid, and the precipitated solid filtered and dried, 4.4 g., m.p. 278°C. dec.

EXAMPLE 7 2-(p-Tolyl)-4-hydroxy-5-carboxypyrimidine (II; Ar = p-CH₃ C₆H₄ and m = 0)

In a manner similar to the procedure of Example 6, 11.9 g. (0.07 mole)of p-toluamidine hydrochloride, 15.12 g. (0.07 mole) of diethylethoxymethylenemalonate and 4.2 g. (0.077 mole) of sodium methoxide in150 ml. of ethanol, after refluxing overnight, provided 9.2 g. of2-(p-toly)-4-hydroxy-5-carbethoxypyrimidine.

Hydrolysis of 5.16 g. (0.02 mole) of the above ester with 2.24 g. ofpotassium hydroxide in 200 ml. of ethanol at reflux temperatures gave4.5 g. of the desired product, m.p. 285° C. dec.

EXAMPLE 8 2-(p-Anisyl)-4-hydroxy-5-carboxypyrimidine (II; Ar = p-CH₃ OC₆H₄ and m = 0)

An ethanol (100 ml.) suspension of 10.0 g. (0.062 mole) of p-anisamidinehydrochloride, 13.4 g. (0.062 mole) diethyl ethoxymethylenemalonate and3.68 g. (0.068 mole) of sodium methoxide is heated to reflux overnight.The solids from the filtered solution are suspended in water andacidified with 6N hydrochloric acid to give 9.9 g. of the esterintermediate, m.p. 224°-226° C.

Treatment of 4.5 g. of the above intermediate with 2.0 g. of potassiumhydroxide in 200 ml. of ethanol and 50 ml. of water at refluxtemperatures gave, on acidification of the cooled reaction solution, 4.3g. of the desired product, m.p. 274° C. dec.

EXAMPLE 9 2-(p-Methoxybenzyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =p-CH₃ OC₆ H₄ and m = 1)

A reaction mixture comprising 10 g. (0.05 mole) ofp-methoxyphenylacetamidine hydrochloride, 10.8 g. (0.05 mole) of diethylethoxymethylenemalonate and 3.0 g. (0.055 mole) of sodium methoxide in100 ml. of ethanol is heated to reflux overnight. The mixture isfiltered and the filtrate concentrated in vacuo to a yellow oil, whichon trituration with 150 ml. of water at pH 1 solidifies, 8.0 g., m.p.107°-111° C. Recrystallization from ethyl acetate gave 5.4 g., m.p.147°-149° C.

Hydrolysis of 2.88 g. of the above ester with 1.12 g. of potassiumhydroxide in 150 ml. of ethanol and 30 ml. of water gave, onacidification to pH 1 of the concentrated reaction mixture, 1.85 g. ofthe desired product as the hydrochloride salt. Conversion to theamphoteric product is carried out by back-adjusting an aqueous solutionof the acid addition salt with a 1N sodium hydroxide solution to pH 2.

EXAMPLE 10

Employing the procedure of Examples 5 through 9, and starting with theappropriate aryl- or arylmethylamidine, the following congeners areprepared: 2-Benzyl-4-hydroxy-5-carboxypyrimidine,2-(o-tolyl)-4-hydroxy-5-carboxypyrimidine,2-(o-methylbenzyl)-4-hydroxy-5-carboxypyrimidine,2-(p-methylbenzyl)-4-hydroxy-5-carboxypyrimidine,2-(o-methoxybenzyl)-4-(hydroxy-5-carboxypyrimidine,2-(m-anisyl)-4-hydroxy-5-carboxypyrimidine and2-(o-anisyl)-4-hydroxy-5-carboxypyrimidine.

EXAMPLE 11 2-(p-Chlorophenyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =p-ClC₆ H₄ and m = O)

Sodium methoxide (3.14 g.; 0.05 mole) is added to a suspension of 10.0g. (0.052 mole) of p-chlorobenzamidine hydrochloride and 11.4 g. (0.052mole) of diethyl ethoxymethylenemalonate in 100 ml. of ethanol, and theresulting reaction mixture heated to reflux overnight. The mixture iscooled and the precipitated solid slurried in water rendered acid to pH1.0 with 6N hydrochloric acid. The ester intermediate is filtered anddried, 7.4 g., m.p. 231°-233° C.

By previously described hydrolysis procedures, 4.18 g. (15 m moles) ofthe above ester and 1.68 g. (30 m moles) of potassium hydroxide in 180ml. of ethanol and 35 ml. of water yield, after 3.0 hrs. at reflux andwork-up, 4.3 g. of product, m.p. 312° C. dec.

EXAMPLE 12

Employing the procedures of Examples 5 through 9 and 11, and startingwith the requisite amidine, the following analogs are synthesized:

    Ar          m         Ar           m                                          ______________________________________                                        o-ClC.sub.6 H.sub.4 --                                                                    0        o-FC.sub.6 H.sub.4 --                                                                       n                                          m-ClC.sub.6 H.sub.4 --                                                                    0        m-FC.sub.6 H.sub.4 --                                                                       0                                          m-ClC.sub.6 H.sub.4 --                                                                    1        m-FC.sub.6 H.sub.4 --                                                                       1                                          p-ClC.sub.6 H.sub.4 --                                                                    1        p-FC.sub.6 H.sub.4 --                                                                       0                                          o-ClC.sub.6 H.sub.4 --                                                                    1        p-FC.sub.6 H.sub.4 --                                                                       1                                          ______________________________________                                    

EXAMPLE 13 2-(m-Nitrophenyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =m-NO₂ C₆ H₄ and m = O)

A mixture of 27.0 g. (0.135 mole) of m-nitrobenzamidine hydrochloride,29.2 g. (0.135 mole) of diethyl ethoxymethylenemalonate and 8.0 g.(0.148 mole) of sodium methoxide in 190 ml. of ethanol is heated toreflux overnight, and is then cooled in an ice bath. The precipitatedsolid is filtered, suspended in 350 ml. of water and treated withsufficient 6N hydrochloric acid to provide a pH of 1.5. The intermediateester is filtered and recrystallized from methanol, 8.0 g., m.p.184°-187° C.

The above ester (4.34 g., 15 m moles) is hydrolyzed to the desired acidby the aforementioned procedure, employing 1.68 g. (30 m moles) ofpotassium hydroxide in 180 ml. of ethanol and 35 ml. of water and areflux time 6.5 hrs., to yield 3.1 g., m.p. 288° C. dec.

EXAMPLE 14

The procedure of Example 13 is repeated, starting with the appropriateamidines, to provide the following congeners:

2-(o-Nitrophenyl)-4-hydroxy-5-carboxypyrimidine,2-(o-nitrobenzyl)-4-hydroxy-5-carboxypyrimidine,2-(m-nitrobenzyl)-4-hydroxy-5-carboxypyrimidine,2-(p-nitrophenyl)-4-hydroxy-5-carboxypyrimidine and2-(p-nitrobenzyl-4-hydroxy-5-carboxypyrimidine.

EXAMPLE 15 2-(3,4-Dimethoxyphenyl)-4-hydroxy-5-carboxypyrimidine (II; Ar= 3,4-(CH₃ O)₂ C₆ H₃ and m = O)

After heating a mixture of 8.0 g. (37 m moles) of3,4-dimethoxybenzamidine hydrochloride, 8.0 g. (37 m moles) of diethylethoxymethylenemalonate and 2.16 g. (40 m moles) of sodium methoxide in175 ml. of ethanol at reflux temperature overnight, the resulting solidsare filtered and suspended in water. The pH of the suspension isadjusted to approximately 1.0 using 6N hydrochloric acid and theprecipitate filtered and dried, 4.1 g., m.p. 225°-227° C.

The above intermediate ester is hydrolyzed by heating 3.04 g (10 mmoles) with 1.1 g. (20 m moles) of potassium hydroxide in 100 ml. ofethanol and 25 ml. of water to yield 2.54 g. of product, m.p. 278°C.dec.

In a similar manner are prepared:2-(3,4-Dimethoxybenzyl)-4-hydroxy-5-carboxypyrimidine (II; Ar = 3,4-(CH₃O)C₆ H₃ and m = 1), m.p. 185° C. dec. and2-(3,4,5,-trimethoxyphenyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =3,4,5-(CH₃ O)₃ C₆ H₂ and m = 0), m.p. 234° C. dec.

EXAMPLE 16 2-(p-Hydroxyphenyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =p-HOC₆ H₄ and m = 0)

In a manner similar to previous examples, 6.0 g. (35 m moles) ofp-hydroxybenzamidine, 7.6 g. (35 m moles) of diethylethoxymethylenemalonate and 2.1 g. (39 m moles) of sodium methoxidegives 7.3 g. of the ester intermediate 3.9 g. of which is converted onhydrolysis to 1.7 g. of the desired product, m.p. 310° C. dec.

Similarly are prepared2-(m-hydroxyphenyl)-4-hydroxy-5-carboxypyrimidine,2-(o-hydroxybenzyl)-4-hydroxy-5-carboxypyrimidine and2-(p-hydroxybenzyl)-4-hydroxy-5-carboxypyrimidine.

EXAMPLE 17 2-(m-Acetamidophenyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =p-CH₃ CONHC₆ H₄ and m = 0)

A suspension of 2.89 g. (0.01 mole) of2-(m-nitrophenyl)-4-hydroxy-5-carbethoxypyrimidine, prepared in Example13, and 350 mg. of platinum oxide in 200 ml. of methanol is shaken in anatomsphere of hydrogen at an initial pressure of 45 p.s.i. When thetheoretical amount of hydrogen has been absorbed, the catalyst isfiltered and the filtrate concentrated in vacuo.

The crude residual 2-(m-aminophenyl)-4-hydroxy-5-carbethoxypyrimidine isheated for 4.5 hrs. in 150 ml. of ethanol containing 1.12 g. (0.02 mole)of potassium hydroxide and 25 ml. of water. The mixture is concentratedunder reduced pressure to a small volume and sufficient 6N hydrochloricacid added such that the aqueous phase is just acid to Congo red paper.The resulting solid, 2-(m-aminophenyl-4-hydroxy-5-carboxypyrimidine, isfiltered and dried.

Without further purification, 1.65 g. (5 m moles) of2-(m-aminophenyl)-4-hydroxy-5-carboxypyrimidine in 25 ml. of ethylacetate, to which is added 1.1 g. of acetic anhydride, is heated toreflux for 3 hrs. The reaction mixture is subsequently cooled in an icebath, and the precipitated product filtered, dried and recrystallizedfrom a large volume of methanol.

EXAMPLE 18

Starting with the appropriate2-(nitrophenyl-4-hydroxy-5-carbethoxypyrimidine esters prepared inExamples 13 and 14 and requisite alkanoic anhydrides, and repeating theprocedure of Example 17, the following analogs are prepared:

    Ar            m        Ar            m                                        ______________________________________                                        m-CH.sub.3 CH.sub.2 CONHC.sub.6 H.sub.4 --                                                  0      p-CH.sub.3 CONHC.sub.6 H.sub.4 --                                                             0                                        o-CH.sub.3 CONHC.sub.6 H.sub.4 --                                                           0      p-CH.sub.3 CH.sub.2 CONHC.sub.6 H.sub.4 --                                                    0                                        o-CH.sub.6 CONHC.sub.6 H.sub.4 --                                                           1      p-CH.sub.3 CONHC.sub.6 H.sub.4 --                                                             1                                        o-CH.sub.3 CH.sub.2 CONHC.sub.6 H.sub.4 --                                                  1      p-CH.sub.3 CH.sub.2 CONHC.sub.6 H.sub.4 --                                                    1                                        ______________________________________                                    

EXAMPLE 19 2-(4'-Pyridyl)-4-hydroxy-5-carboxypyrimidine (II; Ar =4-pyridyl and m = 0)

A mixture of 41.8 g. (0.25 mole) of 4-guanylpyridine hydrochloride, 54.0g. (0.25 mole) of diethyl ethoxymethylenemalonate and 14.9 g. (0.275mole) of sodium methoxide in 200 ml. of methanol is heated to reflux for21 hrs. The suspended solids are filtered and the filtrate concentratedto an oil under reduced pressure. Water is added to the residual oil andthe solids remaining out of solution are filtered, 3.2 g., m.p.195°-198° C. The aqueous filtrate is extracted at pH 10 with chloroformand then adjusted to pH 4, forming additional solids, 2.2 g., m.p.195°-198° C. The aqueous is extracted with chloroform on the acid side(pH 4) and the chloroform layer subsequently concentrated to neardryness, 700 mg., m.p. 195°-200° C.

The initially isolated crops are combined and triturated with ethanol,5.0 g., and the product isolated from the chloroform extractrecrystallized from methanol, to provide the analytical sample, 670 mg.,m.p. 198°-200° C.

Anal. Calc'd for C₁₂ H₁₁ O₃ N₃ : C, 58.8; H, 4.5; N, 17.1. Found: C,58.5; H, 4.5; N , 17.3.

The above intermediate ester (2.45 g.; 0.01 mole) is heated at refluxtemperatures with 1.12 g. (0.02 mole) of potassium hydroxide in 120 ml.of ethanol and 25 ml. of water for 4 hrs. The solvent is removed invacuo and the residual soft solid dissolved in 50 ml. of water. Additionof 6N hydrochloric acid to pH 4 precipitates the desired product whichis filtered and dried, m.p. >320° C.

In a similar manner, starting with the appropriate reagents, areprepared:

2-(2'-Pyridyl)-4-hydroxy-5-carboxypyrimidine (II; Ar = 2-pyridyl and m =0) m.p. 208° C. dec. and 2-(3'-pyridyl)-4-hydroxy-5-carboxypyrimidine(II; Ar = 3-pyridyl and m = 0) m.p. 310° C. dec.

EXAMPLE 20

The procedure of Example 19 is repeated, starting with the requisiteamidine, to provide the following products:2-(2'-pyridylmethyl)-4-hydroxy-5-carboxypyrimidine,2-(4'-pyridylmethyl)-4-hydroxy-5-carboxypyrimidine,2-(2'-thienyl)-4-hydroxy-5-carboxypyrimidine,2-(2'-thenyl)-4-hydroxy-5-carboxypyrimidine,2-(3'-thenyl)-4-hydroxy-5-carboxypyrimidine,2-(2'-furfuryl)-4-hydroxy-5-carboxypyrimidine,2-(3'-furfuryl)-4-hydroxy-5-carboxypyrimidine and2-(2'-furyl)-4-hydroxy-5-carboxypyrimidine.

EXAMPLE 21 Tablets

A tablet base is prepared by blending the following ingredients in theproportion by weight indicated:

           Sucrose, U.S.P.                                                                              80.3                                                           Tapioca Starch 13.2                                                           Magnesium Stearate                                                                            6.5                                                

Into this tablet base there is blended sufficient2-(p-methoxyphenyl)-4-hydroxy-5-carboxypyrimidine to provide tabletscontaining 20, 100 and 250 mg. of active ingredient per tablet. Thecompositions are each compressed into tablets, each weighing 360 mg., byconventional means.

EXAMPLE 22 Capsules

A blend is prepared containing the following ingredients:

    Calcium carbonate, U.S.P.                                                                             17.6                                                  Dicalcium phosphate     18.8                                                  Magnesium trisilicate, U.S.P.                                                                         5.2                                                   Lactose, U.S.P.         5.2                                                   Potato starch           5.2                                                   Magnesium stearate A    0.8                                                   Magnesium stearate B    0.35                                              

To this blend is added sufficient2-(p-methoxyphenyl)-4-hydroxy-5-carboxypyrimidine to provide capsulescontaining 10, 25 and 50 mg. of active ingredient per capsule. Thecompositions are filled into conventional hard gelatin capsules in theamount of 350 mg. per capsule.

EXAMPLE 23 Injectable Preparation

One thousand grams of1,2-bis(4[4'-hydroxy-5'-carboxy-2'-pyrimidinyl]-phenoxy)ethane disodiumsalt are intimately mixed and ground with 2500 grams of sodiumascorbate. The ground dry mixture is placed in vials and sterilized withethylene oxide after which the vials are sterilely stoppered. Forintravenous administration, sufficient water is added to the materialsin the vials to form a solution containing 5.0 mg. of active ingredientper milliliter of injectable solution.

EXAMPLE 24 Solution

A solution of 2-(p-methoxyphenyl)-4-hydroxy-5-carboxypyrimidine sodiumsalt is prepared with the following composition:

    Effective ingredient  6.04     grams                                          Magnesium chloride hexahydrate                                                                      12.36    grams                                          Monoethanolamine      8.85     ml.                                            Propylene glycol      376.00   grams                                          Water, distilled      94.00    ml.                                        

The resultant solution has a concentration of effective ingredient of 10mg./ml. and is suitable for parenteral and especially for intramuscularadministration.

EXAMPLE 25 Suspension

A suspension of 2-(p-methoxyphenyl)-4-hydroxy-5-carboxypyrimidine isprepared with the following composition:

    Effective ingredient                                                                             25.00 g.                                                   70% aqueous sorbitol                                                                            741.29 g.                                                   Clycerine, U.S.P. 185.35 g.                                                   Gum acacia (10% solution)                                                                       100.00 ml.                                                  Polyvinylpyrrolidone                                                                             0.50 g.                                                    Distilled water   Sufficient to make 1 liter                              

To this suspension, various sweeteners and flavorants are added toimprove the palatability of the suspension. The suspension containsapproximately 25 mg. of effective agent per milliliter.

What is claimed is:
 1. A method of preventing asthmatic symptoms in ahuman who is subject to bronchoconstriction which comprisesadministering to said human an asthmatic symptom preventing amount of acompound of the formula ##SPC3##or a pharmaceutically acceptable basicsalt thereof wherein Ar is furyl and m is an integer of 0 to
 1. 2. Themethod of claim 1 wherein said symptoms are the result of allergicasthma.
 3. The method of claim 2 wherein Ar is 2-furyl and m is 0.